ABTRACT Sickle cell disease (SCD) is a genetic disorder of public health significance with high prevalence, high mortality rate and limited interventions. Advancement in genomic research offers an unprecedented opportunity to address the health challenges of SCD in an integrated manner. Cardiac involvement is common in sickle cell disease (SCD) and is associated with increased mortality. The main causes of cardiovascular (CV) morbidity and mortality in SCD are chronic vaso-occlusion with ischemia and cardiac dysfunction, chronic hemolytic anaemia and secondary iron overload from chronic red blood cells transfusion. These culminate in the development of cardiac chamber dilation, and a compensatory increase in left ventricular (LV) mass; left ventricular diastolic dysfunction, dysrhythmia and pulmonary hypertension (PH) leading to right ventricular (RV) dysfunction, and sudden death. In addition, adults with SCD have significantly higher systolic and mean systemic blood pressures if they have pulmonary arterial hypertension (PAH), than in those without PAH. The genetic susceptibility to the development of some of these CV abnormalities also seems to be related to the severe hemolysis in SCD. Although some genetic variants have been described to be associated with both PH and diastolic dysfunction in SCD, genetic studies associated with these echo-CV phenotypes have not been reported in SCD patients who reside in Africa. There is a need to provide a thorough appreciation of the genetic diversity that underlies CV phenotypic heterogeneity in SCD patients in Africa. Knowledge of these factors will help to identify genes and pathways that might be therapeutically manipulated in novel treatment approaches. The overarching goal of this study is to identify common genetic variants associated with diastolic dysfunction and PH in adults with SCD. This will be achieved through three inter-related specific aims. We will study large cohorts of adult SCD patients enrolled in a 4 institution in Nigeria and Tanzania. Specifically we will define the genome-wide genetic determinants of major echo-cardiovascular phenotypes (cardiac dilation, cardiac index, blood pressure, diastolic dysfunction, tricuspid jet regurgitation velocity (TRJV) and RV dysfunction) (Aim 1). We will determine whether genome-wide SNPs associated with the level of hemolysis cytoprotective proteins to be defined in a companion project to this application are linked to specific echo-CV phenotypes (Aim 2). Finally, we will functionally validate using transgenic sickle mice, the associations between the level of cytoprotective proteins and diastolic dysfunction, PH and relative systemic hypertension in SCD (Aim 3). This project will be the first characterizing genetics associated with diastolic dysfunction and PH in SCD patients residing in Africa. It will have high translational potential and may provide mechanistic insight into cardiac disease in SCD and suggest new therapeutic targets that can be exploited for clinical translation.